Variants at different sites in the same gene can be found with distinct frequencies in affected individuals, and both kinase-activating and kinase-impairing variants, especially in CFC-associated B-RAF, can lead to ERK phosphorylation and pathway activation (Garnett et al., 2005; Aoki et al., 2008; Anastasaki et al., 2009; Heidorn et al., 2010; Freeman et al., 2013). The gene discussed is MAPK1; the disease is cardiofaciocutaneous syndrome.